AUTHOR AND EDITOR INFORMATION

Section 1 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

INTRODUCTION

Section 2 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

Background

Gastric cancer is the second most common cause of cancer-related death in the world. Many Asian countries, including Korea, China, Taiwan, and Japan, have very high rates of gastric cancer. Gastric cancer was the leading cause of cancer deaths in men and the third leading cause of cancer deaths in women in the early 1940s. In 2007, 21,260 new cases of gastric cancer (13,000 men; 8,260 women) will be diagnosed with stomach cancer in the United States, and 11,210 persons (6,610 men; 4,600 women) will die of the disease, making gastric cancer the 14th most common cancer in this country. The median age for gastric cancer in the United States is 70 years for males and 74 years for females. Also in the United States, Asian and Pacific Islander males and females have the highest incidence of stomach cancer, followed by black, Hispanic, white, American Indian, and Inuit populations.

Gastric cancer remains a difficult disease to cure in Western countries, primarily because most patients present with advanced disease. Even patients who present in the most favorable condition and who undergo curative surgical resection often die of recurrent disease. Two recent studies have demonstrated improved survival with adjuvant therapy; a US study using postoperative chemoradiation¹ and a European study using preoperative and postoperative chemotherapy.²

The molecular biology responsible for carcinogenesis, tumor biology, and response to therapy are active areas of investigation but are not addressed in this review. Instead, this article focuses on clinical management, which first requires a thorough understanding of gastric anatomy.

The stomach begins at the gastroesophageal junction and ends at the duodenum. The stomach has 3 parts. The uppermost part of the stomach is the cardia, and the largest and middle part is called the body. The distal portion of the stomach, the pylorus, connects to the duodenum. These anatomic zones have distinct histologic features. The cardia contains predominantly mucin-secreting cells. The fundus (ie, body) contains mucoid cells, chief cells, and parietal cells, while the pylorus is composed of mucus-producing cells and endocrine cells.

The stomach wall is made up of 5 layers. From the lumen out, the layers include the mucosa, the submucosa, the muscularis layer, the subserosal layer, and the serosal layer. The peritoneum of the greater sac covers the anterior surface of the stomach. A portion of the lesser sac drapes posteriorly over the stomach. The gastroesophageal junction has limited or no serosal covering. The right portion of the anterior gastric surface is adjacent to the left lobe of the liver and the anterior abdominal wall. The left portion of the stomach is adjacent to the spleen, the left adrenal gland, the superior portion of the left kidney, the ventral portion of the pancreas, and the transverse colon.

The site of the cancer is classified on the basis of its relationship to the long axis of the stomach. Approximately 40% of cancers develop in the lower part, 40% in the middle part, and 15% in the upper part, and 10% involve more than one part of the organ. Over the past half century or so, there has been a steady decline in gastric cancer incidence and gastric cancer deaths in men and women in the United States. Most of this decrease has occurred in the intestinal type of gastric cancer. In addition,  the incidence of gastric cardia adenocarcinoma has actually gradually increased.

The decrease in gastric cancer incidence may be attributed in part to the adoption of diets high in vegetables and fruit. The widespread use of refrigeration contributes to the decline in incidence by reducing the intake of salt, which had been used as a food preservative, and decreasing the contamination of food by carcinogenic compounds arising from the decay of unrefrigerated meat products. Salt and salted foods may cause damage to the gastric mucosa with resultant inflammation associated with increase in DNA synthesis and cell proliferation.

Pathophysiology

Understanding the vascular supply of the stomach allows understanding of the routes of hematogenous spread. The vascular supply of the stomach is derived from the celiac artery. The left gastric artery, a branch of the celiac artery, supplies the upper right portion of the stomach. The common hepatic artery branches into the right gastric artery, which supplies the lower portion of the stomach, and the right gastroepiploic branch, which supplies the lower portion of the greater curvature.

Understanding the lymphatic drainage can clarify the areas at risk for nodal involvement by cancer. The lymphatic drainage of the stomach is complex. Primary lymphatic drainage is along the celiac axis. Minor drainage occurs along the splenic hilum, suprapancreatic nodal groups, porta hepatis, and gastroduodenal areas.

Frequency

United States

Gastric cancer is the seventh leading cause of cancer deaths. More than 22,000 new cases are diagnosed each year, of which 11,430 are expected to die. In 2007, 21,260 new cases of gastric cancer (13,000 men; 8,260 women) will be diagnosed with stomach cancer in the United States, and 11,210 persons (6,610 men; 4,600 women) will die of the disease.

International

Adenocarcinoma of the stomach is the second most common cancer worldwide. In 2001, stomach cancer affected 850,000 people, of which 522,000 men and 328,000 women died of stomach cancer. According to data collected by the World Health Organization, the most common forms of cancer worldwide (excluding nonmelanoma skin cancers) are lung (12.3%), breast (10.4%), and colorectum (9.4%), while the top 3 causes of death from cancer are lung (17.8%), gastric (10.4%), and liver (8.8%). Tremendous geographic variation exists in the incidence of this disease around the world. The highest death rates are recorded in Chile, Japan, South America, and the former Soviet Union.

Mortality/Morbidity

The 5-year survival rate for curative surgical resection ranges from 30-50% for patients with stage II disease and from 10-25% for patients with stage III disease. Because these patients have a high likelihood of local and systemic relapse, some physicians offer them adjuvant therapy. The operative mortality rate for patients undergoing curative surgical resection at major academic centers is less than 3%.

Race

The rates of gastric cancer are higher in Asian and South American countries than in the United States. Japan, Chile, and Venezuela have developed a very rigorous early screening program that detects patients with early stage disease (ie, low tumor burden). These patients appear to do quite well. In fact, in many Asian studies, patients with resected stage II and III disease tend to have better outcomes than similarly staged patients treated in Western countries. Some researchers suggest that this reflects a fundamental biologic difference in the disease as it manifests in Western countries.

In the United States, Asian and Pacific Islander males and females have the highest incidence of stomach cancer, followed by black, Hispanic, white, American Indian, and Inuit populations.

Sex

Gastric cancer affects slightly more men than women.

Age

Most patients are elderly at diagnosis. The median age for gastric cancer in the United States is 70 years for males and 74 years for females. The gastric cancers that occur in younger patients may represent a more aggressive variant.

CLINICAL

Section 3 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

History

• In the United States, about 25% of stomach cancer cases present with localized disease, 31% present with regional disease, and 32% present with distant metastatic disease; the remainder of cases surveyed were listed as unstaged.
• Early disease has no associated symptoms; however, some patients with incidental complaints are diagnosed with early gastric cancer. Most symptoms of gastric cancer reflect advanced disease. Patients may complain of indigestion, nausea or vomiting, dysphagia, postprandial fullness, loss of appetite, melena, hematemesis, and weight loss.
• Late complications include pathologic peritoneal and pleural effusions; obstruction of the gastric outlet, gastroesophageal junction, or small bowel; bleeding in the stomach from esophageal varices or at the anastomosis after surgery; intrahepatic jaundice caused by hepatomegaly; extrahepatic jaundice; and inanition resulting from starvation or cachexia of tumor origin.

Physical

• All physical signs are late events, and almost invariably the signs develop too late for curative procedures.
• Signs may include a palpable enlarged stomach with succussion splash; hepatomegaly; periumbilical metastasis (Sister Mary Joseph nodule); enlarged lymph nodes such as: Virchow nodes (ie, left supraclavicular), Irish node (anterior axillary); and Blumer shelf (ie, shelflike tumor of the anterior rectal wall). Some patients experience weight loss and others may present with melena or pallor from anemia.
• Paraneoplastic syndromes such as dermatomyositis, acanthosis nigricans, and circinate erythemas are poor prognostic features.
• Other associated abnormalities also include peripheral thrombophlebitis and microangiopathic hemolytic anemia.

Causes

Several factors are implicated in the development of gastric cancer, including diet, Helicobacter pylori infection, previous gastric surgery, pernicious anemia, adenomatous polyps, chronic atrophic gastritis, prior radiation exposure or inherited syndromes. Gastric cancer may often be multifactorial involving both inherited predisposition and environmental factors.³

• Diet
  
  
  • A diet rich in pickled vegetables, salted fish, excessive dietary salt, and smoked meats correlates with an increased incidence of gastric cancer.³
  • A diet that includes fruits and vegetables rich in vitamin C may have a protective effect.⁴
• Smoking
  
  
  • Smoking is associated with an increased incidence of stomach cancer in a dose-dependent manner, both for number of cigarettes and duration of smoking.
  • Smoking increases the risk of cardiac and noncardiac forms of stomach cancer. Cessation of smoking reduces the risk.
  • A meta-analysis of 40 studies estimated that the risk was increased by approximately 1.5- to 1.6-fold and was higher in men.⁵
• Helicobacter pylori infection
  
  
  • Chronic bacterial infection with H pylori is the strongest risk factor for stomach cancer.
  • H pylori may infect 50% of the world's population, but much less than 5% of infected individuals develop cancer. It may be that only a particular strain of H pylori, one which is capable of producing the greatest amount of inflammation, is especially associated with the risk of malignancy. The full malignant transformation of affected parts of the stomach may require that the human host have a particular genotype of interleukin-Iβ to cause the increased inflammation and an increased suppression of gastric acid secretion.
• • H pylori infection is associated with chronic atrophic gastritis, and patients with a history of prolonged gastritis have a 6-fold increase in their risk of developing gastric cancer. Interestingly, this association is particularly strong for tumors located in the antrum, body, and fundus of the stomach but does not seem to hold for tumors originating in the cardia.⁶
• Previous gastric surgery
  
  
  • Previous surgery is implicated as a risk factor. The rationale is that surgery alters the normal pH of the stomach which may in turn lead to metaplastic and dysplastic changes in luminal cells.⁷
  • Retrospective studies demonstrate that a small percentage of patients who undergo gastric polyp removal have evidence of invasive carcinoma within the polyp. This discovery has led some researchers to conclude that polyps might represent premalignant conditions.
• Genetic factors
  
  
  • Some 10% of stomach cancer cases are familial in origin.
  • Genetic factors involved in gastric cancer remain poorly understood, though specific mutations have been identified in a subset of gastric cancer patients. For example, germ-line truncating mutations of the E-cadherin gene are detected in 50% of diffuse-type gastric cancers and families that harbor these mutations have an autosomal dominant pattern of inheritance with a very high penetrance.⁸
  • Other hereditary syndromes with a predisposition for stomach cancer include hereditary nonpolyposis colorectal cancer, Li-Fraumeni syndrome, familial adenomatous polyposis, and Peutz-Jeghers syndrome. 
  • Ebstein-Barr virus: The Epstein-Barr virus may be associated with an unusual form of stomach cancer (<1%), lymphoepitheliomalike carcinoma.
  • Pernicious anemia: Pernicious anemia associated with advanced atrophic gastritis and intrinsic factor deficiency is a risk factor for gastric carcinoma.
• Gastric ulcers
  
  
  • Gastric cancer may develop in the remaining portion of the stomach following a partial gastrectomy for gastric ulcer.
  • Benign gastric ulcers may themselves develop into malignancy.  
• Obesity: Obesity increases the risk of gastric cardiac cancer.
• Radiation exposure: Atomic bomb survivors exposed to radiation have had an increased risk of stomach cancer. Other populations exposed to radiation may also have an increased risk of stomach cancer.

DIFFERENTIALS

Section 4 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

WORKUP

Section 5 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

Lab Studies

• The goal of obtaining laboratory studies is to assist in determining optimal therapy.
• A complete blood cell count can identify anemia, which may be caused by bleeding, liver dysfunction, or poor nutrition. Approximately 30% of patients have anemia.
• Electrolyte panels and liver function tests also are essential to better characterize the patient's clinical state.
• Carcinoembryonic antigen (CEA) is increased in 45-50% of cases.
• Cancer antigen (CA) 19-9 is elevated in about 20% of cases.

Imaging Studies

• Esophagogastroduodenoscopy has a diagnostic accuracy of 95%.  
  
  
  • This relatively safe and simple procedure provides a permanent color photographic record of the lesion.
  • This procedure is also the primary method for obtaining a tissue diagnosis of suspected lesions. Biopsy of any ulcerated lesion should require at least 6 biopsies taken from around the lesion because of variable malignant transformation.
  • In selected cases, endoscopic ultrasound may be helpful in assessing depth of penetration of the tumor or involvement of adjacent structures.
• Double-contrast upper gastrointestinal series and barium swallows may be helpful in delineating the extent of disease when obstructive symptoms are present or when bulky proximal tumors prevent passage of the endoscope to examine the stomach distal to an obstruction (more common with gastroesophageal [GE]-junction tumors). These studies are only 75% accurate and should for the most part be used only when upper GI endoscopy is not feasible.
• Chest radiograph is done to evaluate for metastatic lesions.
• CT scan or MRI of the chest, abdomen, and pelvis assess the local disease process as well as evaluate potential areas of spread (ie, enlarged lymph nodes, possible liver metastases).
• Endoscopic ultrasound allows for a more precise preoperative assessment of the tumor stage.
  
  
  • Endoscopic sonography is becoming increasingly useful as a staging tool when the CT scan fails to find evidence of T3, T4, or metastatic disease.
  • Institutions that favor neoadjuvant chemoradiotherapy for patients with locally advanced disease rely on endoscopic ultrasound data to improve patient stratification.

Histologic Findings

Adenocarcinoma of the stomach constitutes 90-95% of all gastric malignancies. The second most common gastric malignancies are lymphomas. Gastrointestinal stromal tumors formerly classified as either leiomyomas or leiomyosarcomas account for 2% of gastric neoplasms (see Gastric Stromal Tumors). Carcinoids (1%), adenoacanthomas (1%), and squamous cell carcinomas (1%) are the remaining tumor histologic types.

• Adenocarcinoma of the stomach is subclassified according to histologic description as follows: tubular, papillary, mucinous, or signet-ring cells, and undifferentiated lesions.
• Pathology specimens are also classified by gross appearance. In general, researchers consider gastric cancers ulcerative, polypoid, scirrhous (ie, diffuse linitis plastica), superficial spreading, multicentric, or Barrett ectopic adenocarcinoma.
• Researchers also employ a variety of other classification schemes. The Lauren system classifies gastric cancer pathology as either Type I (intestinal) or Type II (diffuse). An appealing feature of classifying patients according to the Lauren system is that the descriptive pathologic entities have clinically relevant differences.
  
  
  • Intestinal, expansive, epidemic-type gastric cancer is associated with chronic atrophic gastritis, retained glandular structure, little invasiveness, and a sharp margin. The pathologic presentation classified as epidemic by the Lauren system is associated with most environmental risk factors, carries a better prognosis, and shows no familial history.
  • The second type, diffuse, infiltrative, endemic cancer, consists of scattered cell clusters with poor differentiation and dangerously deceptive margins. Margins that appear clear to the operating surgeon and examining pathologist often are determined retrospectively to be involved. The endemic-type tumor invades large areas of the stomach. This type of tumor is also not recognizably influenced by environment or diet, is more virulent in women, and occurs more often in relatively young patients. This pathologic entity is associated with genetic factors (such as E-cadherin), blood groups, and a family history of gastric cancer.

Staging

The 2006 American Joint Committee on Cancer (AJCC) Cancer Staging Manual presents the following TNM classification system for staging gastric carcinoma:

• Primary tumor
  
  
  • TX - Primary tumor (T) cannot be assessed
  • T0 - No evidence of primary tumor
  • Tis - Carcinoma in situ, intraepithelial tumor without invasion of lamina propria
  • T1 - Tumor invades lamina propria or submucosa
  • T2 - Tumor invades muscularis propria or subserosa
  • T3 - Tumor penetrates serosa (ie, visceral peritoneum) without invasion of adjacent structures
  • T4 - Tumor invades adjacent structures
• Regional lymph nodes
  
  
  • NX - Regional lymph nodes (N) cannot be assessed
  • N0 - No regional lymph node metastases
  • N1 - Metastasis in 1-6 regional lymph nodes
  • N2 - Metastasis in 7-15 regional lymph nodes
  • N3 - Metastasis in more than 15 regional lymph nodes
• Distant metastasis
  
  
  • MX - Distant metastasis (M) cannot be assessed
  • M0 - No distant metastasis
  • M1 - Distant metastasis
• Prognostic features
  
  
  • Two important factors influencing survival in resectable gastric cancer are depth of cancer invasion through the gastric wall and presence or absence of regional lymph node involvement.
  • In about 5% of primary gastric cancers, a broad region of the gastric wall or even the entire stomach is extensively infiltrated by malignancy, resulting in a rigid thickened stomach, termed linitis plastica. Linitis plastica has an extremely poor prognosis.⁹
  • Margins positive for presence of cancer are associated with a very poor prognosis.
  • The greater the number of involved lymph nodes, the more likely the patient is to develop local and systemic failure after surgery.
  • In a study by Shen and colleagues,¹⁰ the depth of tumor invasion and gross appearance, size, and location of the tumor were 4 pathological factors independently correlated with the number of metastatic lymph nodes associated with gastric cancer.
• Staging
  
  
  • Stage 0 - Tis, N0, M0
  • Stage IA - T1, N0 or N1, M0
  • Stage IB - T1, N2, M0 or T2a/b, N0, M0
  • Stage II - T1, N2, M0 or T2a/b, N1, M0 or T2, N0, M0 
  • Stage IIIA - T2a/b, N2, M0 or T3, N1, M0 or T4, N0, M0
  • Stage IIIB - T3, N2, M0
  • Stage IV - T1-3, N3, M0 or T4, N1-3, M0, or any T, any N, M1
• Survival rates
  
  
  • Stage 0 - Greater than 90%
  • Stage Ia - 60-80%
  • Stage Ib - 50-60%
  • Stage II - 30-40%
  • Stage IIIa - 20%
  • Stage IIIb - 10% 
  • Stage IV - Less than 5%.
• Spread patterns
  
  
  • Cancer of the stomach can spread directly, via lymphatics, or hematogenously.
  • Direct extension into the omenta, pancreas, diaphragm, transverse colon or mesocolon, and duodenum is common.
  • If the lesion extends beyond the gastric wall to a free peritoneal (ie, serosal) surface, then peritoneal involvement is frequent.
  • The visible gross lesion frequently underestimates the true extent of the disease.
  • The abundant lymphatic channels within the submucosal and subserosal layers of the gastric wall allow for easy microscopic spread.
  • The submucosal plexus is prominent in the esophagus and the subserosal plexus is prominent in the duodenum, allowing proximal and distal spread.
  • Lymphatic drainage is through numerous pathways and can involve multiple nodal groups (eg, gastric, gastroepiploic, celiac, porta hepatic, splenic, suprapancreatic, pancreaticoduodenal, paraesophageal, and paraaortic lymph nodes).
  • The cancer also spreads hematogenously, and liver metastases are common.

TREATMENT

Section 6 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

Surgical Care

• Type of surgery 
  
  • In general, most surgeons in the United States perform a total gastrectomy (if required for negative margins), an esophagogastrectomy for tumors of the cardia and gastroesophageal junction, and a subtotal gastrectomy for tumors of the distal stomach. 
    
  
  
  • A randomized trial comparing subtotal with total gastrectomy for distal gastric cancer revealed similar morbidity, mortality, and 5-year survival rates.¹¹ 
    
  
  
  • Because of the extensive lymphatic network around the stomach and the propensity for this tumor to extend microscopically, traditional teaching is to attempt to maintain a 5-cm surgical margin proximally and distally to the primary lesion. 
    


• Lymph node dissection 
  
  • The extent of the lymph node dissection is somewhat controversial. 
    
  
  
  • Many studies demonstrate that nodal involvement indicates a poor prognosis, and more aggressive surgical approaches to attempt to remove involved lymph nodes are gaining popularity. 
    
  
  
  • Two randomized trials compared D1 (perigastric lymph nodes) with D2 (hepatic, left gastric, celiac and splenic arteries as well as those in the splenic hilum) lymphadenectomy in patients who were treated for curative intent. In the largest of these trials, postoperative morbidity (43% versus 25%) and mortality (10% versus 4%) were higher in the D2 group.^{12, 13} 
    
  
  
  • Most critics argue that these studies were underpowered and overestimated benefit. Despite negative results of randomized trials, D2 dissections continue to be done and are recommended by the National Comprehensive Cancer Network over D1 dissections. A pancreas and spleen-preserving D2 lymphadenectomy is suggested as it provides greater staging information, and may provide a survival benefit while avoiding its excess morbidity when possible. 
    


• Outcome 
  
  • The 5-year survival rate for a curative surgical resection ranges from 60-90% for patients with stage I, 30-50% for patients with stage II disease, and 10-25% for patients with stage III disease. 
    
  
  
  • Because these patients have a high likelihood of local and systemic relapse, some physicians offer adjuvant therapy.
    

Consultations

• Specialists recommend obtaining consultations freely in the management of most malignancies, and gastric carcinoma is no exception. The gastroenterologist, surgical oncologist, radiation oncologist, and medical oncologist work closely as a team.

FOLLOW-UP

Section 7 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

Deterrence/Prevention

A diet that includes fruits and vegetables rich in vitamin C may have a protective effect.

Complications

• Direct mortality rate within 30 days after a surgical procedure for gastric cancer has been reduced substantially over the last 40 years. Most major centers report a direct mortality rate of 1-2%.
• Early postoperative complications include anastomotic failure, bleeding, ileus, transit failure at the anastomosis, cholecystitis (often occult sepsis without localizing signs), pancreatitis, pulmonary infections, and thromboembolism. Further surgery may be required for anastomotic leaks.
• Late mechanicophysiologic complications include dumping syndrome, vitamin B-12 deficiency, reflux esophagitis, and bone disorders, especially osteoporosis.
• Postgastrectomy patients often are immunologically deficient as measured by blastogenic and delayed cutaneous hypersensitivity responses.

Prognosis

• Unfortunately, only a minority of patients with gastric cancer who undergo a surgical resection will be cured of their disease. The majority of patients have a recurrence.


• Patterns of failure 
  
  • Several studies have investigated the patterns of failure after surgical resection alone. Studies that depend solely on the physical examination, laboratory studies, and imaging studies may overestimate the percentage of patients with distant failure and underestimate the incidence of local failure, which is more difficult to detect. 
    
  
  
  • A reoperation series from the University of Minnesota may offer a more accurate understanding of the biology of the disease. In this series of patients, researchers surgically reexplored patients 6 months after the initial surgery and meticulously recorded the patterns of disease spread. The total local-regional failure rate approached 67%. The gastric bed was the site of failure in 54% of these cases, and the regional lymph nodes were the site of failure in 42%. Approximately 22% of patients had evidence of distant failure. The patterns of failure included local tumor regrowth, tumor bed recurrences, regional lymph node failures, and distant failures (ie, hematogenous failures and peritoneal spread). Primary tumors involving the gastroesophageal junction tended to fail in the liver and the lungs. Lesions involving the esophagus failed in the liver.


• Adjuvant therapy: The pattern of failure prompted a number of investigations into adjuvant therapy. The rationale behind radiotherapy is to provide additional local-regional tumor control. Adjuvant chemotherapy is used either as a radiosensitizer or as definitive treatment for presumed systemic metastases. 
  
  • Adjuvant radiotherapy 
    
    • Moertel and colleagues randomized postoperative patients with advanced gastric cancer to receive 40 Gray (Gy) of radiotherapy or 40 Gy of radiotherapy with 5-FU as a radiosensitizer and demonstrated improved survival associated with the combined modality therapy.¹⁴ 
      
    
    
    • The British Stomach Cancer Group reported lower rates of local recurrence in patients who received postoperative radiotherapy than in those who underwent surgery alone.¹⁵
      
    
    
    • The update of the initial Gastrointestinal Tumor Study Group series revealed higher 4-year survival rates in patients with unresectable gastric cancer who received combined modality therapy than in those who received chemotherapy alone (18% vs 6%).¹⁶ 
      
    
    
    • A series from the Mayo Clinic randomized patients to receive postoperative radiotherapy with 5-FU or surgery alone and demonstrated improved survival in the patients receiving adjuvant therapy (23% vs 4%).¹⁷ 
  
  
  • Intraoperative radiotherapy 
    
    • Some authors suggest that intraoperative radiotherapy (IORT) shows promising results. 
      
    
    
    • This alternative method of delivering radiotherapy allows for a high dose to be given in a single fraction while in the operating room so that other critical structures can be avoided. 
      
    
    
    • The National Cancer Institute randomized patients with grossly resected stage III/IV gastric cancer to receive either 20 Gy of IORT or 50 Gy of postoperative external beam. Local failure was delayed in the patients treated with IORT (21 mo vs 8 mo). Although the median survival duration also was higher (21 mo vs 10 mo), this figure did not reach statistical significance.¹⁸
  
  
  • Adjuvant chemotherapy  
    
    
    • Numerous randomized clinical trials comparing combination chemotherapy in the postoperative setting to surgery alone did not demonstrate a consistent survival benefit. 
      
      
    • Recent meta-analyses have shown a hint of statistical benefit. In one meta-analysis of 13 randomized trials, adjuvant systemic chemotherapy was associated with a significant survival benefit (odds ratio for death, 0.80; 95% CI, 0.66-0.97). In subgroup analysis, there was a trend toward a larger magnitude of effect for trials in which at least two-thirds of the patients had node-positive disease.¹⁹
      
      
    • A postoperative chemoradiation study was prompted in part by the patterns of failure studies demonstrating local failure often preceding systemic spread. 
  • Adjuvant chemoradiotherapy 
    
    • A randomized phase III study performed in the United States known as Intergroup 0116 demonstrated a survival benefit associated with postoperative chemoradiotherapy compared with surgery alone.¹ 
      
    
    
    • In this study, patients underwent an en bloc resection. 
      
    
    
    • Patients with T3 and/or N+ adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive bolus 5-fluorouracil (5-FU) and leucovorin (LV) and radiotherapy or observation.
      
    
    
    • Patients who received the adjuvant chemoradiotherapy demonstrated improved disease free-survival (from 32% to 49%) and improved overall survival rates (from 41% to 52%) compared to those who were merely observed.
      
    
    
    • This regimen is considered the standard of care in the United States. 
  
  
  • Neoadjuvant chemotherapy
    
    
    • Neoadjuvant chemotherapy may allow downstaging of disease to increase resectability, decrease micrometastatic disease burden prior to surgery, allow patient tolerability prior to surgery, determine chemotherapy sensitivity, reduce the rate of local and distant recurrences, and ultimately improve survival.
      
      
    • A European randomized trial also demonstrated survival benefit when patients were treated with 3 cycles of preoperative chemotherapy (epirubicin, cisplatin, and 5-fluorouracil) followed by surgery and then 3 cycles of postoperative chemotherapy compared with surgery alone. The benefit was comparable to that obtained with postoperative chemoradiation in the US trial.² However, the Gastric Chemotherapy Group for Japan did not demonstrate a significant survival benefit with neoadjuvant chemotherapy. 
      
      
    • Choice of preoperative and postoperative chemotherapy versus postoperative chemotherapy and radiation remains controversial, and an ongoing United States Intergroup study, CALGB 80101, will look more closely at that question. 
       
      
• Advanced unresectable disease  
  
  
  • Many patients present with distant metastases, carcinomatosis, unresectable hepatic metastases, pulmonary metastases, or direct infiltration into organs that cannot be resected completely. 
    
  
  
  • In the palliative setting, radiotherapy provides relief from bleeding, obstruction, and pain in 50-75% of patients. The median duration of palliation is 4-18 months. 
    
  
  
  • Surgical procedures such as wide local excision, partial gastrectomy, total gastrectomy, simple laparotomy, gastrointestinal anastomosis, and bypass also are performed with palliative intent, with a goal of allowing oral intake of food and alleviating pain. 
    
  
  
  • A standard management technique has been cisplatin-based chemotherapy, but results have been largely discouraging with median time to progression of 3-4 months and overall survival of approximately 6-9 months despite response rates of up to 45% reported. Early results reported in 2007 by Japanese clinicians suggest some improvement in both response rates and survival with the oral fluoropyrimidine S-1 used alone or in combination with cisplatin. (S-1 combines 3 investigational drugs: tegafur, a prodrug of 5-FU; gimeracil, an inhibitor of fluorouracil degradation; and oteracil or potassium oxanate, a GI tract adverse effect modulator.) These results remain to be confirmed by ongoing studies in Europe and North America. 
    
  
  
  • Platinum-based chemotherapy in combinations such as epirubicin/cisplatin/5-FU or docetaxel/cisplatin/5-FU represents the current first-line chemotherapies. Other active regimens include irinotecan and cisplatin and other combinations with oxaliplatin and irinotecan. 
    
  
  
  • Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF) is currently being evaluated for use in advanced gastric cancer.²⁰

Patient Education

For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education article, Stomach Cancer.

REFERENCES

Section 8 of 8

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

1. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. Sep 6 2001;345(10):725-30. [Medline].
2. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. Jul 6 2006;355(1):11-20. [Medline].
3. Correa P. Diet modification and gastric cancer prevention. J Natl Cancer Inst Monogr. 1992;75-8. [Medline].
4. Buiatti E, Palli D, Decarli A, Amadori D, Avellini C, Bianchi S, et al. A case-control study of gastric cancer and diet in Italy. Int J Cancer. Oct 15 1989;44(4):611-6. [Medline].
5. González CA, Pera G, Agudo A, Palli D, Krogh V, Vineis P, et al. Smoking and the risk of gastric cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). Int J Cancer. Nov 20 2003;107(4):629-34. [Medline].
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Article Last Updated: Jul 23, 2007